From cellular receptors to transduction-transcription pathways for cytokines: at which level should the inhibition be targeted in inflammation?

An imbalance in cytokine homeostasis is considered to play a major part in the pathogenesis of immuno-inflammatory diseases. Since the identification and cloning of cytokines and their receptors, therapeutic approaches have been developed with the purpose of impeding the interaction between the ligand (cytokine) and its specific receptor, or interactions that involve the use of anti-inflammatory cytokines to switch off inflammation. Although some diseases have been treated successfully with cytokines or anticytokines (i.e., anti-TNF, and to a lesser extent recombinant IL-1 receptor antagonist, in rheumatoid arthritis; IFN-beta in multiple sclerosis), the fact remains that these therapies do not abrogate the concomitant use of steroids or immunosuppressive drugs, and that a significant percentage of patients do not respond to such therapies; these are important limitations. The identification of signalling pathways preferentially used in inflammatory conditions has boosted approaches that target these intracellular mechanisms. This review examines the different therapeutic approaches that may be considered for the treatment of immuno-inflammatory diseases, and discusses the advantages and disadvantages of targeting extracellular or intracellular mechanisms.